A Hypoxia-Activated Photomolecular Glue with Synergistic Cyclin K Degradation and Phototherapy for Cancer Treatment
Shuai Li1, Zhenzhen Tian2, Yan Ma1
1Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, Nanjing 210009, China.
Abstract:
Cyclin K is overexpressed in multiple tumors and plays critical roles in tumorigenesis, making it a promising therapeutic target. Although the antitumor potential of Cyclin K-targeting molecular glues, their clinical application is limited by insufficient efficacy and tumor selectivity. Herein, we developed BNNC, a photomolecular glue that releases Cyclin K molecular glue (R)-CR8 and phototherapeutic agent BSS-Et in hypoxic tumor microenvironments, thereby enhancing tumor selectivity. Network pharmacology and Western blotting analysis demonstrated that the combination of (R)-CR8 and BSS-Et synergistically enhances DNA damage and apoptosis in breast cancer cells compared to either monotherapy. In vivo, BNNC exhibited potent tumor growth inhibition with excellent biosafety and biocompatibility. This intelligent design framework significantly improves the therapeutic efficacy and selectivity of molecular glues. It is expected to be generalizable to other molecular glues and phototherapeutic agents.
Insights
We developed BNNC, a novel photomolecular glue that targets Cyclin K. BNNC enhances tumor selectivity and efficacy by releasing therapeutic agents in hypoxic tumor microenvironments, showing potent antitumor activity.
Area of Science:
- Oncology
- Molecular Biology
- Drug Development
Background:
- Cyclin K is overexpressed in tumors, presenting a therapeutic target.
- Current Cyclin K-targeting molecular glues lack sufficient efficacy and tumor selectivity.
- Hypoxic tumor microenvironments offer opportunities for targeted drug delivery.
Purpose of the Study:
- To develop a novel photomolecular glue (BNNC) for enhanced tumor selectivity and efficacy.
- To leverage hypoxic tumor microenvironments for targeted release of therapeutic agents.
- To evaluate the synergistic effects of combined therapies and in vivo performance.
Main Methods:
- Development of BNNC, a photomolecular glue releasing (R)-CR8 and BSS-Et.
- Network pharmacology and Western blotting to analyze molecular mechanisms.
- In vitro studies on breast cancer cells to assess DNA damage and apoptosis.
- In vivo studies to evaluate tumor growth inhibition, biosafety, and biocompatibility.
Main Results:
- BNNC selectively releases (R)-CR8 and BSS-Et in hypoxic tumor microenvironments.
- The combination of (R)-CR8 and BSS-Et synergistically enhanced DNA damage and apoptosis in breast cancer cells.
- BNNC demonstrated potent tumor growth inhibition in vivo.
- BNNC exhibited excellent biosafety and biocompatibility.
Conclusions:
- BNNC represents an intelligent design framework for improved molecular glue therapy.
- Photomolecular glues can enhance therapeutic efficacy and selectivity through targeted delivery.
- This approach is potentially generalizable to other molecular glues and phototherapeutic agents for cancer treatment.
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